The overall goal of this project is to understand how retroviruses adversely affect the central nervous system. We are utilizing the mouse as an animal model and are currently focusing our attention on a virus, CasBrE, which causes a non-inflammatory spongiform encephalomyelopathy similar in its pathologic features to the transmissible spongiform encephalopathies (TSE) diseases caused by prion agents. Transcriptinal profiling using microarray techology has revealed that Endoplasmic Reticulum (ER) Stress responses may be involved in the pathogenesis of this disease. During the past year we have focused our attention on identifying the cause of this ER stress. We have found that the virus itself induces the response and, using biochemical and fluorescence imaging analyses, have found that this response is induced by the instability and misfolding of the viral envelope protein within the ER. This finding is important because previous work by us and others has shown that the viral envelope protein harbors the determinants of neurovirulence. We are currently studying the down-stream effects of the ER stress responses induced by this virus. These include effects on calcium fluxes, redox balance, amino acid availability as well as proteasome function. These studies are important because ER stress has now been shown to be associated with a variety of acquired and heritable degenerative diseases of humans, including Parkinsons disease, Huntingtons disease and one variety of heritable TSE disease. Understanding the nature of the cellular stress responses induced by CasBrE, and the connection between these responses and the neuronal cytopathology induced by this virus, promises to uncover important biochemical pathways to which therapeutic intervention can be directed.